The continuing objective of this proposal is to identify and characterize fundamental mechanisms that underlie the organization of synaptic circuits in the central nervous system. Of particular interest in this regard is how local synaptic circuits segregate in order to support the parcellation of the nervous system into functional domains. In this context, local circuits refer specifically to those whose synaptic connections are confined or restricted to a limited region of the nervous system. During the prior period of support we have continued to employ the olfactory system as an efficacious model for addressing these questions. The current proposal seeks to build upon the knowledge gained during the prior period of support and to test specific hypotheses regarding the organization and connectivity of olfactory bulb afferent input and glomerular circuits. There is general agreement that olfactory bulb glomeruli constitute a basic anatomical unit of odor organization in the olfactory bulb. This is accomplished, in part, by the distribution of primary afferents to specific glomeruli, a topographic pattern that is very complex. Although significant reorganization and mixing of axons occurs between the epithelium and bulb, within the nerve, it is not yet clear where, along the length of the nerve, reorganization occurs and what molecular cues may initiate the process. Within the glomeruli there are multiple dendritic targets including subpopulations of both projection- and inter-neurons. Preliminary evidence suggests that innervation of a glomerulus by a single axon is not uniform and therefore, that the intraglomerular distribution of primary afferents onto heterogeneous targets may support subglomerular organization. To explore these controversial questions more fully we propose to test the following hypotheses: 1) Defasciculation and reorganization of olfactory receptor cell axons within the olfactory nerve occurs as a result of a change in the affinity or number of cell surface adhesion molecules. 2) The reorganization of axons within the oIfactory nerve supports the establishment of fascicles of axons that share molecular specificity. 3) The distribution of olfactory receptor cell axons within a glomerulus is not homogeneous. Individual fascicles define subglomeruIar compartments; axons within individual fascicles can be characterized, in part, by common or shared molecular markers. Subglomerular compartments can also be characterized, in part, by a predominance of axodendritic versus dendrodendritic synaptic circuits. 4) Intaglomerular synaptic organization is heterogeneous. Synaptic density and topological distribution differ among subpopulations of both projection- and inter-neurons. To address these issues we will employ immunocytochemistry and the selective impregnation of single neurons for analysis with light microscopy, scanning laser confocal microscopy, and conventional and high voltage transmission electron microscopy. The results will be widely applicable for understanding parcellation throughout the nervous system and in disease states such as Alzheimer's or Kallman's where there are known olfactory sequelae. In addition, the results will be applicable to temporal lobe epilepsy where the low threshold for olfactory bulb seizure activity may contribute to the etiology of epileptiform disease.